Oxidative modifications of S100 proteins: functional regulation by redox

Several S100 Ca2-binding proteins undergo various post-translational modifications that may alter their intra-cellular and extracellular functions. S100A8 and S100A9, two members of this family, are particularly susceptible to oxidative modification. These proteins, abundantly ex-pressed in neutrophils and activated macrophages, are associated with acute and chronic inflammatory condi-tions, including microbial infections, cystic fibrosis, rheu-matoid arthritis, and atherosclerosis. They have diverse intracellular roles including NADPH oxidase activation and arachidonic acid transport and can be secreted via a Golgi-independent pathway to exert extracellular func-tions. Many pro-inflammatory functions have been de-scribed for S100A8 and S100A9, but they are also impli-cated in anti-inflammatory roles in wound-healing and protection against excessive oxidative tissue damage, the latter as a result of their exquisite capacity to scav-enge oxidants. Similarly, their genes are induced by proinflammatory (LPS and TNF-) stimuli, but induction is IL-10-dependent, and anti-inflammatory glucocorticoids induce or amplify expression. S100A8 and S100A9 were described recently as damage-associated molecular pat-tern molecules, which provide a novel, conceptual frame-work for understanding their functions. However, be-cause of this designation, recent reviews focus solely on their pro-inflammatory functions. Here, we summarize the mounting evidence from functional and gene regula-tion studies that these proteins may also play protective roles. This review offers an explanation for the disparate, functional roles of S100A8 and S100A9 based on emerg-ing data that post-translational, oxidative modifications may act as a regulatory switch. J. Leukoc. Biol. 86: 577–587; 2009